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A Broader Role for Amyloids

Amyloids are best known for their role in diseases such as Alzheimer’s. A new study finds that amyloids may also have a normal biological function.

A cell from the pituitary gland stores the hormones
it produces in granules (green). All rights reserved
by Wellcome Images.

Alzheimer’s and other related diseases are marked by clumps
of protein fibers that accumulate around nerve cells in the brain.
These dense plaques are made of proteins that are normally found
in the body but have misfolded to form amyloids. Amyloid can
also cause problems beyond the brain. For example, they can form
waxy protein deposits that stiffen the heart, limiting its pumping
ability and leading to fatal heart stoppage.

Amyloids are actually defined by their structure, not the specific
proteins that form them. They are made of highly organized protein
arrangements called β-sheets that stack perpendicularly
along the axis of the amyloid fiber.

A research team led by Dr. Roland Riek of the Salk Institute
for Biological Studies noted that structures called secretory
granules also have a highly ordered organization. Secretory granules
allow cells that secrete hormones and other molecules to store
those molecules in a highly concentrated form. With funding from
NIH’s National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK), the researchers explored whether protein
hormones could form amyloids.

The scientists exposed 42 hormones in the lab to conditions
similar to that in the Golgi complex, the part of the cell where
secretory granules form. In the June 18, 2009, online edition
of Science, they reported that, at first, 10 of the
hormones formed amyloids. However, when they added a type of
molecule known to be involved in forming both secretory granules
and amyloids, 31 of the hormones formed amyloids.

Amyloids are notoriously stable, but secretory granules must
release their molecular contents in order to work properly. The
researchers thus exposed the amyloids they’d made to the
conditions they would experience upon being secreted. All the
hormone amyloids appeared to release their component hormones
under these conditions. Further tests revealed the hormones to
be functional.

Since amyloids are thought to be toxic to neuronal cells, the
researchers tested whether the ones they’d created were
toxic to a neuronal cell line in the laboratory. Some proved
moderately toxic. But the scientists noted that their actual
toxicity in the body could be substantially lower, because they’re
stored inside granules and encapsulated by a membrane.

The researchers next examined secretory granules purified from
a pituitary tumor cell line and from rat pituitary tissue. Both
types appeared to be composed of amyloids. Amyloids also appeared
to be present in secretory granules in mouse pituitary tissue.

These experiments provide evidence that secretory granules
contain amyloids, and that amyloids help the body store and release
hormones. Previous research has found that amyloids also play
a role in forming melanin, which helps protect the skin from
sun damage. Together, these studies suggest that amyloids may
play normal roles throughout the body. It may not be amyloids
themselves that cause disease, but rather conditions that lead
too much amyloid to form in the wrong places. Future research
will be needed to better understand the role of these molecular
structures in disease.